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Summary of the impact

International obstetric practice has been changed by two large randomised
controlled trials led from the University of Oxford's National Perinatal
Epidemiology Unit, which demonstrated the efficacy of magnesium sulphate
for both treatment and prevention of eclampsia during pregnancy, a
condition characterised by fits in association with hypertension, and an
important cause of maternal morbidity and mortality. Until the 1990s there
was widespread geographical variation in the management of the condition,
with magnesium sulphate used almost exclusively in North America.
Following the publication of the results of these two trials magnesium
sulphate is now in routine use globally, widely recommended in guidelines,
and has been placed on the WHO Model List of Essential Medicines.

Underpinning research

Eclampsia represents the gravest end of the spectrum of hypertensive
disorders in pregnancy. Usually preceded by pre-eclampsia, eclampsia is
characterised by grand mal seizures, coma, hypertension, proteinuria and
oedema, and can lead to maternal death. In 1992, with 383 affected women
nationally, an Oxford-led study demonstrated that the rate of eclampsia
was 5 per 10,000 women delivering in the UK. One in 50 of these affected
women died from the disorder [1]. During this period eclampsia was a
leading cause of maternal morbidity and mortality globally, responsible
for an estimated 50,000 maternal deaths annually worldwide. Standard
treatment at that time in the UK and many other countries was with an
anticonvulsant such as diazepam or phenytoin, whereas in North America,
magnesium sulphate was principally used. Clinicians elsewhere were
sceptical about the efficacy of magnesium sulphate as there was
insufficient randomised controlled trial evidence to support its use.

In 1995, the Collaborative Eclampsia trial of magnesium sulphate for the
treatment of women having an eclamptic fit was led by Dr Lelia
Duley and co-ordinated from the National Perinatal Epidemiology Unit
(NPEU), University of Oxford. In this international multi-centre
randomised controlled trial, conducted in nine countries, 1,687 women
having an eclamptic fit were randomised to receive magnesium sulphate,
diazepam or phenytoin [2]. The trial demonstrated a statistically
significant halving in the recurrence of seizures for women treated with
magnesium sulphate compared with diazepam and phenytoin. There were also
non-significant reductions in maternal mortality, severe maternal
morbidity, and fetal and neonatal effects.

The Oxford-led `Magpie Trial', published in 2002, was a multi-centre
international randomised controlled trial of magnesium sulphate for the prevention
of eclampsia. This trial also demonstrated the benefits of magnesium
sulphate in halving the risk of eclampsia in women with pre-eclampsia who
were treated with magnesium sulphate [3]. In the absence of an existing
preventive therapy, 10,141 women with pre-eclampsia across 33 countries
were randomised to receive either magnesium sulphate or placebo. A
cost-effectiveness study was subsequently conducted, using the Magpie
Trial data. This demonstrated that the number of women with pre-eclampsia
who needed to be treated to prevent one case of eclampsia was 324 in high
resource settings, 184 in medium and 43 in low resource settings [4]. When
treatment was used for severe pre-eclampsia the incremental cost (that is
the amount of additional spending on magnesium needed) of preventing one
case of eclampsia was $12,942 in high resource settings, $1,179 in medium
resource settings and $263 in low resource settings.

A national study conducted by the NPEU in 2005 demonstrated a halving in
the observed incidence of eclampsia in the UK following the introduction
of magnesium sulphate treatment for severe pre-eclampsia, with a
two-thirds reduction in the incidence of the associated severe maternal
morbidity [5]; the effect sizes were at the level predicted by the
original Eclampsia Collaborative and Magpie trials.

References to the research

[1]. Douglas KA, Redman CW. Eclampsia in the United Kingdom. Br Med J
1994;309:1395-400. doi: 10.1136/bmj.309.6966.1395. PubMed ID: 7819845. This
paper reports the first UK national study estimating the incidence of
eclampsia prior to the publication of the eclampsia trials and is
provided for background.

[2]. The Eclampsia Trial Collaborative Group. Which anticonvulsant for
women with eclampsia? Evidence from the Collaborative Eclampsia Trial.
Lancet 1995; 345: 1455-63.
PubMed ID: 7769899. The first of two key papers, theCollaborative
Eclampsia Trialdemonstrates the clinical effectiveness of
magnesium sulphate for the treatment of eclampsia compared
with standard treatment.

[5]. Knight M on behalf of UKOSS. Eclampsia in the United Kingdom 2005.
BJOG. 2007;114(9):1072-8.
PubMed ID: 17617191. This paper reports the second and most recent
UK national study estimating the incidence of eclampsia following the
introduction of magnesium sulphate into clinical practice for the
prevention and management of eclampsia and is provided to complete the
picture of evidence.

This research was funded by the UK Medical Research Council, the UK
Department for International Development, the UNDP/UNFPA/WHO/World Bank
Special Programme of Research, Development and Research Training in Human
Reproduction (HRP) and the European Commission.

Details of the impact

National Impact:
The Royal College of Obstetricians & Gynaecologists incorporated the
findings into their clinical guidelines (2006) for the management of both
severe pre-eclampsia and eclampsia, and these continued to be the national
guidance followed until 2010 [A]. This guidance was superseded by NICE
guidelines which cite the studies and recommend use of magnesium sulphate
for treatment of both eclampsia and severe pre-eclampsia [A]. We estimate
that two hundred cases of eclampsia per year are now prevented in the UK
amongst an estimated 40,000 pre-eclamptic women treated with magnesium
sulphate, and whilst deaths do occur, they are now extremely rare [B].

Global Impact:
WHO recommendations for the prevention and treatment of pre-eclampsia and
eclampsia recommend magnesium sulphate for the prevention and treatment of
eclampsia, specifically citing these studies [C]. Other national
guidelines in high resource countries also cite the studies while making
the same recommendations [D]. The Pre-Eclampsia/Eclampsia: Prevention,
Detection and Management toolkit for Developing Countries was
developed by the USAID-funded Maternal and Child Health Integrated Program
(MCHIP) as a resource of current evidence, materials and experiences from
around the world and cites the studies as the key evidence behind the
recommendation to use magnesium sulphate for the prevention and treatment
of pre-eclampsia and eclampsia [E].

A recent systematic review [F] demonstrated that in Bangladesh, India,
Pakistan, and Nigeria in addition to the UK, the introduction of treatment
for eclampsia with magnesium sulphate as a result of these trials
consistently results in a halving of the rates of maternal death.
Magnesium sulphate is now included on the WHO Model List of Essential
Medicines [G] and was recently added to the Interagency Emergency Health
Kit of recommended medicines and medical devices for 10,000 people for
approximately three months [H].

Magnesium sulphate continues to be introduced in low resource countries
internationally, as part of initiatives aimed at reaching Millennium
Development Goal 5, to reduce maternal mortality by three-quarters by
2015. For example, a recent Department for International Development
intervention in Tanzania included the provision of magnesium sulphate as
one of four key actions [I].

Sources to corroborate the impact

[A]. NICE Guideline CG107 (issued August 2010). The management of
hypertensive disorders during pregnancy. http://www.nice.org.uk/nicemedia/live/13098/50418/50418.pdf
[Accessed 6/9/2013]. This is the current UK national guidance
recommending use of magnesium sulphate to prevent eclampsia and
referencing the studies in the supporting evidence. See section 1.8.

[B]. Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, et al.
(2011) Saving Mothers' Lives: Reviewing maternal deaths to make motherhood
safer: 2006-2008. The Eighth Report of the Confidential Enquiries into
Maternal Deaths in the United Kingdom. BJOG 118 Suppl 1: 1-203. PubMed ID:
21356004. This reports cases of maternal death in the UK and shows
the rarity of deaths from eclampsia. It nevertheless cites the Oxford
University research to emphasise the importance of magnesium sulphate
to prevent eclampsia. See pages 68 & 70.

[D]. Society of Obstetricians and Gynecologists of Canada Clinical
Practice Guideline. Diagnosis, Evaluation, and Management of the
Hypertensive Disorders of Pregnancy (2008). http://sogc.org/wp-content/uploads/2013/01/gui206CPG0803hypertensioncorrection.pdf
[Accessed 06/09/2013]. An example of a national guideline also
recommending magnesium sulphate for the management and prevention of
eclampsia. See sections S5 & S32.

[G]. WHO Model List of Essential Medicines (2011). http://whqlibdoc.who.int/hq/2011/a95053_eng.pdf
[Accessed 06/09/2013]. WHO list of recommended essential medicines
for health services listing magnesium sulphate for the treatment of
eclampsia and management of severe pre-eclampsia. See p 4.

[H]. WHO Interagency Emergency Health Kit (2011). http://whqlibdoc.who.int/publications/2011/9789241502115_eng.pdf
[Accessed 06/09/2013]. Details of WHO Interagency Emergency Health
Kit 2011 — Medicines and medical devices for 10,000 people for
approximately three months. Magnesium sulphate included in 2011
version for treatment of eclampsia/pre-eclampsia. See page 6.

[I]. Department for International Development (2011). Business Case and
Intervention Summary — Reproductive and Maternal Health Supplies in
Tanzania. http://devtracker.dfid.gov.uk/projects/GB-1-202959/documents/
[Accessed 06/09/2013]. This describes the DFID intervention
for 2012-14 in Tanzania, citing the Magpie study as evidence for the
provision of magnesium sulphate to prevent maternal death. See
Evidence section — Clinical effectiveness of maternal health supplies.